Sustained release formulations of lorazepam

ABSTRACT

A pharmaceutical composition for delivering lorazepam in a prolonged fashion is achieved with prolonged release lorazepam pharmaceutical beads. The composition typically contains sustained release lorazepam beads and delayed sustained release lorazepam beads. The composition can provide once daily dosing that maintains 24 hour therapeutic effect under steady state conditions.

The present application claims the benefit of priority under 35 U.S.C.§119(e) from prior U.S. provisional patent application No. 61/750,797,filed on Jan. 9, 2013 and from prior U.S. provisional patent applicationNo. 61/762,833, filed on Feb. 8, 2013; the entire contents of eachprovisional application being incorporated herein by reference.

BACKGROUND OF THE INVENTION

The present invention relates to sustained release formulations oflorazepam and to methods of treating patients with a once-a-day dose oflorazepam.

Lorazepam is the generic name for the active pharmaceutical ingredient±7-chloro-5-(2-chlorophenyl)-1,3-dihydro-3-hydroxy-2H-1,4-benzodiazepin-2-one,which has the following structure:

Like other benzodiazepines, lorazepam has CNS activity and has proven tobe a useful treatment for anxiety related disorders, such as: GeneralAnxiety Disorder or Anxiety associated with Major Depression and others.It is almost insoluble in water. This compound was disclosed in U.S.Pat. No. 3,296,249.

Lorazepam has been sold commercially under the brand name ATIVAN®(originally by Wyeth, now by Valeant Intl) in the form of an oralimmediate release tablet. The tablets contain 0.5 mg, 1 mg, or 2 mg oflorazepam and are usually administered two or three times a day (b.i.dand t.i.d, respectively) to achieve a total dose of 2 to 6 mg/day,though doses from 1 to 10 mg/day can also be used. According to the U.S.package insert material for ATIVAN®: “For anxiety, most patients requirean initial dose of 2 to 3 mg/day given b.i.d. or t.i.d.” The peak plasmaconcentrations (Cmax) typically occur about 2 hours (Tmax) after oraladministration. Lorazepam has, according to the package insert, ahalf-life in human plasma of about 12 hours.

While the immediate release tablets of lorazepam, with a multi-dose perday regimen, have been available for several decades, thus far noonce-a-day dosage form has been commercially introduced. Such a dosageform is often desirable. Besides the benefit of convenience, a sustainedrelease version that could provide 24 hour therapeutic effect, but withlower peak plasma concentration levels than the immediate releasetablet, may reduce side effects. For this reason, Abrams et al.investigated a sustained release tablet containing 2 mg of lorazepam andcompared it to a 2 mg dose of lorazepam immediate release tablets (2×1mg tablets). S. M. L. Abrams et al., “Pharmacodynamic andPharmacokinetic Comparison of Two Formulations of Lorazepam andPlacebo,” Human Psychopharmacology, Vol. 3, 133-138 (1988). Thesustained release tablet had, as expected, a longer Tmax (median 8hours) and a lower Cmax (12 ng/ml) than the immediate release tablets (2hours and 22 ng/ml, respectively). But the relative bioavailability wasreduced in the sustained release tablet such that after 30 hours the AUCwas only about 85% of the AUC achieved with the immediate releasetablets. Abrams et al. also noted that “the [serum] concentrations ofboth formulations were similar between 10 and 30 h[ours].” Thus, despiteproviding some delay in the rise of lorazepam serum concentrations and alower Cmax, the sustained release tablet apparently did not serve toextend the therapeutic duration of lorazepam beyond that achieved withimmediate release tablets.

The long half-life of lorazepam in blood plasma makes it a classicallydisregarded candidate for the development of a once daily formulation.Also, a drug product that provides 24 hour therapy from two doses perday, as opposed to three or more doses per day, is generally consideredto have achieved the majority of patient compliance benefits. If asingle daily dose formulation was desired, an immediate releaselorazepam tablet could be used to provide a complete daily dose becauseof the long half-life of lorazepam in blood plasma. But administering acomplete daily dose in a single immediate release dosage form wouldincrease the Cmax and the peak-trough variations (concentrationdifferences between Cmax and Cmin) beyond those attained in conventionalb.i.d. administration (i.e., twice-daily dosing), and thus would likelyincrease the risk of drug related adverse events, i.e., side effects.Using a sustained release formulation can reduce the rate of increase inplasma drug concentration and the value of Cmax, but runs the risk ofsub-therapeutic plasma concentration levels, especially near the end ofthe dosing cycle, and/or lower overall drug exposure than the currentb.i.d. immediate release tablet regimen.

A lorazepam formulation that provides a sustained release profile withthe potential for an effective and well tolerated once daily dosingregimen would be advantageous.

SUMMARY OF THE INVENTION

The present invention relates to sustained release lorazepamcompositions that provide rather prolonged release of lorazepam. A firstaspect of the invention relates to a pharmaceutical composition,comprising (i) lorazepam sustained release beads and (ii) lorazepamdelayed sustained release beads, wherein the total amount of lorazepamcontained in said composition is 0.5 to 10 mg. The delayed sustainedrelease beads, as explained in more detail below, are sustained releasebeads having a coating that delays the start of the sustained release.Preferred embodiments permit once daily administration of thecomposition with 24 hours of therapeutic effect. Typically the preferredcomposition is a capsule containing the two types of beads, but is notlimited to such.

Another aspect of the invention relates to a sustained release lorazepampharmaceutical composition, which comprises lorazepam prolonged releasebeads in sufficient amount and duration that in a single dosepharmacokinetic study, said composition has a pharmacokinetic profilethat comprises a Tmax at 4 hours or longer and continued absorption oflorazepam beyond 20 hours, preferably for at least 24 hours, morepreferably for at least 28 hours, and still more preferably for at least30 hours; said composition being an oral dosage form containing 0.5 to10 mg of lorazepam. The composition when administered once daily to apatient, maintains a therapeutic effect for at least 24 hours Byproviding a prolonged release dosage form that achieves prolongedabsorption, lorazepam can accumulate in the blood plasma and providefavorable steady state pharmacokinetic profiles.

A further aspect of the invention relates to a method of treating alorazepam-treatable condition in a patient, which comprisesadministering once a day to a patient in need thereof one of theabove-mentioned pharmaceutical compositions in a sufficient dose toprovide 24 hour therapeutic effect during steady state conditions. Thecomposition may comprise (i) lorazepam sustained release beads and (ii)lorazepam delayed sustained release beads, wherein the total amount oflorazepam contained in said composition is 0.5 to 10 mg. Typicallorazepam-treatable conditions include anxiety disorders such asGeneralized Anxiety Disorder and anxiety associated with majordepression, but is not limited thereto.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 represents the dissolution of the lorazepam sustained releasebeads made in Example 1 in a two media dissolution test.

FIG. 2 represents the dissolution of the lorazepam delayed sustainedrelease beads made in Example 2 in a two media dissolution test.

FIG. 3 represents the dissolution of the lorazepam delayed sustainedrelease beads of Example 2 using a different two media dissolution testwherein the second media has a pH of 6.8 instead of 7.4.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to the discovery that sustained releaseformulations of lorazepam that have a rather prolonged release orabsorption characteristic(s) can provide advantageous steady statepharmacokinetic profiles including an effective once-a-day dosingregimen. Surprisingly, by continuing to provide even small amounts oflorazepam late in the dosing cycle, the accumulation of lorazepam in theblood can be sufficiently bolstered and lead to beneficial steady statepharmacokinetic profiles. In this way, the goal of lower Cmax, lowerpeak-trough variation, but proper drug exposure and limited risk ofsub-therapeutic blood levels can be achieved.

One aspect of achieving the prolonged release/absorption of lorazepamrelates to lorazepam formulations comprising two types of sustainedrelease lorazepam beads. The first type begins releasing shortly afteringestion and continues releasing for a prolonged period of time. Thesecond type has a delay owing to a coating that will delay the onset ofrelease from the bead. Once the coating is sufficiently removed and/orpermeable, the delayed sustained release bead begins to release the drugfor a prolonged period of time. By controlling the rate of sustainedrelease in each type of bead, controlling the delay via the coating, andcombining them into a unit dosage form, such as a capsule, it ispossible to provide a once-a-day dosing administration routine with 24hour therapeutic effect. In preferred embodiments, the unit dosage formcontaining the two kinds of beads can have similar or improved efficacyand/or reduced side effects in comparison to the same total dose ofconventional immediate release tablets that are given at least twicedaily or b.i.d. For clarity, dosing regimens, such as once daily, twicedaily or b.i.d., etc., are intended to refer to equal time spacesbetween successive doses. For example, a b.i.d. regimen would mean thedose is administered every 12 hours; a once-a-day dosing regimen wouldmean dosing once every 24 hours; etc.

The lorazepam sustained release beads can be any kind of pharmaceuticalbead, pellet, or other pharmaceutical particulate that containslorazepam and releases the lorazepam in an extended manner. Thissustained or extended release characteristic is in contrast to animmediate release profile which generally requires release of 90% of thelorazepam in 30 minutes as measured in a suitable in vitro dissolutiontest. For purposes of the present invention, a sustained releaselorazepam bead does not release 90% of the lorazepam in less than 2hours in a USP Type I apparatus (Basket) using 0.1 N HCl as thedissolution media.

The sustained release lorazepam beads preferably release 20 to 80%,typically 20 to 70%, more typically 25 to 60%, and often 30 to 50%, ofthe lorazepam in 2 hours. Further, the release profile of thesepreferred beads often includes achieving 90% after 4 hours (i.e., beyondthe 4 hour point of the dissolution test), more typically after 6 hours,and in some embodiments after 8 hours. Indeed, in some rare embodiments,90% release may not actually be achieved in the dissolution test; e.g.,the maximum release in dissolution testing may only be 85%, for example.Such a result would mean that 90% release would not have occurred orbeen achieved before 8 hours as per an embodiment of the invention. Thepoint is that 90% is not released before the specified time point,regardless of whether 90% release was eventually achieved or not. Somepreferred sustained release lorazepam beads are so prolonged that theydo not release 90% of the lorazepam before 10 hours, more preferablybefore 12 hours, and in some embodiments before 13 or even 14 hours. Inmost embodiments, however, 90% release is ultimately achieved andusually occurs before 20 hours, generally by 18 hours and often by oraround 16 hours. In some embodiments, the 90% release occurs before 15hours or even before 14 hours, such as by 12 or 13 hours. Because therelease curve may be relatively flat near the end of the release, smallchanges in the percent amount of released drug may take hours to occur.Accordingly, a broad time window for achieving 90% release maynonetheless include relatively similar release curves. Typical timeframes for achieving 90% release include 8 to 22 hours such as 8 to 20hours or 8 to 18 hours, more typically 10 to 18 hours, and sometimes 12to 16 hours. Often the dissolution profile will include achieving 80%release within the range of 6 to 16 hours, typically 6 to 14 hours, moretypically 6 to 12 hours, and sometimes 7 to 12 hours. In someembodiments, 50% of the lorazepam is released within 1 to 5 hours and70% is released within 4 to 10 hours. While each of the above releaseamount-time relationships can be applied individually, preferredsustained release lorazepam beads of the invention meet any combinationof two or more of the above relationships; e.g., the release curve meets(i) the 20-70% at 2 hours relationship, (ii) the 70% within 4 to 10hours relationship, and (iii) the 90% within 10 to 19 hoursrelationship. Unlike the definition of a sustained release lorazepambead, each of the above-described preferred release relationships forsustained release lorazepam beads is determined/measured using a twomedia in vitro dissolution test using a USP Type I apparatus (Basket).

In the “two media dissolution test,” the first two hours are carried outusing a media that comprises 0.1 N HCl. At 2 hours the media is changedto a media that comprises a phosphate buffer and has a pH of 7.4. As isunderstood in the art, the first media approximates the stomachconditions while the second media approximates the intestinalconditions. Other ingredients can be present in the media, such asenzymes, etc., as is known in the art, e.g., in formulating simulatedintestinal fluid (SIF). The two media dissolution test is conducted at37° C. and can use 500 ml or 900 ml vessels. The stirring speed istypically 100 rpm, though the speed can be adjusted, such as to 75 or 50rpm, etc., if necessary for the dissolution testing to give more usefulinformation for a particular embodiment. For clarity, when options areprovided such as different size vessels, a bead that meets the profilerelease data under any option is considered to meet the releasecriteria; e.g., a bead that exhibits at 2 hours 31% release in a 900 mlvessel but only 27% release in a 500 ml vessel is considered to meet therange of 30 to 50% release at 2 hours because it met the range in one ofthe options. The percentage of lorazepam released is based on thenominal or label amount (e.g., 2 mg), as is conventional in the art, andnot on the actual assayed amount (e.g. 1.96 mg). In a well-controlledprocess, the actual assayed amount is generally within +/−5% of thelabel amount. The percentage of release at a point in time refers to thecumulative release up to that point in time, as per the conventionalusage of these terms in the art. The amount of lorazepam released fromthe beads (i.e., dissolved into the dissolution media), can bedetermined by ordinary methods using routine skill.

The delayed sustained release lorazepam bead comprises a sustainedrelease lorazepam bead, such as those having the preferred in vitrodissolution release profile described above, having an outer coatinglayer that causes a delay in the start of the release. Generally thedelay coating is designed to achieve a release delay in vivo of at least3 hours, often within the range of 4-8 hours, before significant releasestarts. Delay coatings are generally known in the art and are usuallybased on pH, solubility, or a combination. A pH-dependent coating, alsoknown as an enteric coating, changes solubility based on pH. At low pHsuch as found in the stomach, the coating is insoluble and prevents thebody fluids from reaching and releasing the drug from the beads. Athigher pH such as found in the intestines, the coating becomes solubleand is removed and/or becomes permeable thereby permitting the bodyfluids to reach and release the drug from the beads. The delay iscontrolled by the pH at which the coating becomes soluble and by thecoating thickness/amount. A solubility-based coating uses a lowwater-soluble coating that slowly dissolves or erodes to reveal theunderlying bead and thereby permit drug release to start. The solubilityand thickness/amount of the coating control the time of the delay (e.g.,how long until the coating is gone). Both kinds of coating can be usedtogether in a hybrid fashion.

Though delay coatings of various constructions can achieve the sameeffect in vivo, they may provide different results in an in vitrodissolution test, depending upon the conditions, because of their designprinciples. For example, using the two media in vitro dissolution testdescribed above, a pH-dependent delay coating will start to permit drugrelease shortly after the changeover to the pH 7.4 media. Asolubility-based delay coating that is not pH-dependent will not be asaffected by the media changeover.

Using the two media in vitro dissolution test as described above, apH-dependent delay coating should exhibit essentially no lorazepamrelease, i.e., less than 3%, typically less than 1%, and generally lessthan or near the limit of detection, in the first media (e.g. for thefirst 2 hours). In practice, sometimes slightly higher amounts oflorazepam are released during the first two hours; generally not morethan 10%, usually not more than 5%. The delayed sustained release beadshave appreciable release starting in the second media. Preferredembodiments achieve 20 to 80%, often 25 to 50%, release of the lorazepamin 4 hours and optionally further achieve 90% release after 6 hours,more typically after 8 hours, and in some embodiments after 10 hours. Insome embodiments, 50% of the lorazepam is released within 4 to 8 hoursand 70% is released within 7 to 12 hours. Indeed, the preferred releaserelationships described for the sustained release beads can alsodescribe the release from delayed sustained release beads with theaddition of 2 hours onto the time to account for the delay in releaseduring the initial 2 hours in 0.1N HCl. For example, the delayed releaselorazepam bead embodiment where 90% release is not achieved before 10hours is translated to the delayed sustained release bead as notreleasing 90% before 12 hours, e.g., 2 hours later in the dissolutiontest.

For delay coatings that are solubility-based, pH-independent, therelease profile using the two media in vitro dissolution test generallyincludes achieving 10% release not earlier than 2 hours and moretypically not earlier than 4 hours and often at 6 hours or later. Insome embodiments, these delayed sustained release lorazepam beadsachieve 20 to 80% release, and often 25-50% release, of lorazepam in 8hours. Achieving 90% release of lorazepam often occurs after 10 hours,more typically after 12 hours but before 24 hours. For clarity, a delaycoating that has both pH-dependent polymers and pH-independent polymersis considered to be a pH-dependent delay coating.

The pharmaceutical composition containing the two kinds of beads istypically a unit dosage form for oral administration. The beads arefrequently filled into a capsule but can also be mixed with excipientsand compressed into tablets. If desired, the tablets could be bi-layertablets having the sustained release lorazepam beads in one layer andthe delayed sustained release lorazepam beads in the other layer, butsuch is not required. Other compositions including sachets containingthe beads are also possible. The sachet composition, which mayadditionally include excipients such as a sweetener or taste maskingagent, etc., can be swallowed directly from the package or it can besprinkled onto food or deposited into a drink such as water or juice andthen immediately consumed with the food or drink, respectively. Usuallythe composition contains only the two populations of beads: thesustained release lorazepam beads and the delayed sustained releaselorazepam beads. It is possible, however, that additional lorazepam beadtypes or populations are contained. Immediate release lorazepam beadsmay additionally be included, for example. The presence of immediaterelease lorazepam is generally disfavored and, if present, preferablyaccounts for 20% or less, more preferably 10% or less, of the totalamount of lorazepam in the composition. Typically the amount ofimmediate release lorazepam is essentially zero, meaning zero andtrivial amounts not intended to provide therapeutic effect or modulationof the steady state blood plasma concentration and generally less than3%, less than 2%, and less than 1%. In general, when additionallorazepam beads are present, at least 80%, sometimes at least 90%, andin some embodiments at least 95%, of the total amount of lorazepam iscontained in the combination of the sustained release lorazepam beadsand the delayed sustained release lorazepam beads. As stated above, thecombination of sustained release lorazepam beads and the delayedsustained release lorazepam beads typically provide 100% of thelorazepam content in the composition of the invention. In allembodiments, the ratio of sustained release lorazepam beads to delayedsustained release lorazepam beads is not particularly limited and isgenerally from 1:0.5 to 1:4, respectively, based on the amount oflorazepam. Often the ratio is 1:1+/−30%, more typically +/−25%, andsometimes +/−10%. Typically, though not necessarily, lorazepam is theonly active in the composition.

The pharmaceutical composition contains 0.5 to 10 mg of lorazepam.Lorazepam and its synthesis are well known and the drug is generallycommercially available. Lorazepam can be amorphous or crystalline.Though it has a diazepine ring nitrogen that could be used for forming asalt, typically lorazepam is used as a non-salt or free base. Lorazepamis usually presented as a racemic mixture, but an individual isomer ornon-racemic mixtures could also be used. For purposes of the presentinvention, “lorazepam” is intended to embrace all such pharmaceuticalforms of lorazepam including pharmaceutically acceptable salts, racemicand non-racemic forms or individual isomers, crystalline forms thereofincluding hydrates and solvates, and amorphous forms, unless notedotherwise. Typical amounts for commercial reasons are often from 1 to 6mg, especially 1 to 4 mg, including 1 mg, 2 mg, 2.5 mg, 3 mg, and 4 mg;though each integer from 1 to 10, inclusive, also represents suitablespecific dose amounts. In some embodiments, the amount of lorazepam inmilligrams is an integer from 1 to 10 plus (or minus) 0.25 or 0.5 mg.The extra 0.25 or 0.5 can be split evenly between the sustained releaselorazepam beads and the delayed sustained release lorazepam beads.Alternatively the entirety of the extra amount can be in the sustainedrelease lorazepam beads or entirely in the delayed sustained releaselorazepam beads, or any variations in between. For example, informulating a total lorazepam dose of 2.25 mg, 1 mg may be present assustained release lorazepam beads and 1.25 mg may be present as delayedsustained release lorazepam beads (e.g., the extra amount is entirely inthe delayed sustained release lorazepam beads).

Sustained release lorazepam beads can be formulated using any sustainedrelease bead technique, including matrix-based beads or barriercoating-based beads, in order to achieve the desired in vitrodissolution release profile. Matrix-based beads are generally made bygranulating and extruding a mixture comprising the polymer matrixmaterial(s), the lorazepam and optionally additional excipients such asbinders and fillers. Typical polymer matrix materials include, but arenot limited to, various grades of hydroxypropyl methylcellulose (HPMC),polyacrylates such as various Eudragit brand compositions, andpolyethylene oxides. Binders and fillers include starch,microcrystalline cellulose (MCC), etc. The extruded beads are typicallysubject to spheronization and drying. Barrier coating-based beadstypically start with a nonpareil seed core, such as a sugar core or MCCcore, upon which successive functional coating layers are formed. Forinstance, a core could be coated with a sealing coat, followed by a druglayer coat having the drug and a binder, followed by arelease-controlling polymer coat layer (the barrier layer). The barrierlayer is generally, but not limited to, a water insoluble polymer as afilm forming material. Examples include celluloses such as ethylcellulose, and acrylate polymers and copolymers. Additional materialsare usually included to enhance performance of the film. These includebut are not limited to: plasticizer(s) to confer flexibility and ensurethat coat cracking or physical changes do not compromise the drugreleasing properties; antitacking aids to minimize particleadherence/aggregation during processing or storage; dispersants/wettingagents to aid in surface coating; and pore formers where indicated toprovide channels for drug release. In either kind of sustained releasebead, the lorazepam drug content is generally low and typically lessthan 7%, more typically less than 5%, and often 1-4% by weight, based onthe weight of the bead. The sustained release lorazepam beads typicallyhave a size of less than 1 millimeter, and frequently the beads arewithin the size range of 0.4-0.8 millimeters.

The delayed sustained release lorazepam beads are a sustained releaselorazepam bead core having a delay coating layer. The sustained releaselorazepam bead used as the core can be the same as, or different from,the sustained release lorazepam beads used in the first population. Inthe typical embodiment, the delay coating is the well known entericcoating; that is, one based on polymers having pH-dependent solubility.These polymers are insoluble or substantially insoluble in an acidicaqueous media but become more soluble as the pH increases. Generallysuch polymers have free acid groups such as cellulose acetate phthalateor polymethacrylates and their copolymers, but is not limited to such. Auseful enteric coating can be based on Eudragit FS 30 D. Other possibleenteric coating materials include Eudragit S 100 and Eudragit S 12.5.Enteric coatings can be based on a single enteric polymer or acombination and typically further contain a plasticizer. The beads canbe coated by conventional means often via a liquid media which isremoved upon drying to leave the polymer-based coating. The delayedsustained release lorazepam beads are usually a little larger than thesustained release lorazepam beads owing to the coating thickness.Nonetheless, the delayed sustained release lorazepam beads are alsotypically not greater than 1 millimeter and often within the range of0.4 to 0.9.

The enteric coating can prevent release of the drug in the stomachand/or intestine until the enteric coating is sufficiently soluble topermit diffusion, erosion, and/or is dissolved away. By selecting thekind of polymer(s) and the amount of coating, the enteric coating canprovide any desired level of pH protection; e.g. release/soluble at pH6, 6.8, 7, etc. Generally, the present invention prefers an entericcoating that is designed to release at pH 7 or greater, especially aboutpH 7.4. Commercially available enteric coatings are often designated bythe manufacturer as having a release a specified pH. Those designated ashaving a release at pH 7 are thus deemed to be designed to release at pH7 and are sometimes described as providing colon release. In the GItract, the pH gradually increases in the small intestine from pH 6 toabout pH 7.4 in the terminal ileum. In preferred embodiments of thepresent invention, the delayed sustained release lorazepam beads aretargeted to begin releasing in or near the terminal ileum. Even ifdesigned to release at pH 7.4, for instance, enteric coatings aregenerally not perfect and often begin permitting appreciable release ofthe drug before pH 7. For purposes of the present invention, an entericcoating “designed to release at pH 7 or higher” includes those that havea significant reduction in release during hours 2-6 when the two mediadissolution test is modified by replacing the pH 7.4 phosphate buffermedia with pH 6.8 phosphate buffer media. A significant reduction is atleast 50%. For example, if the delayed sustained release bead released30% of the lorazepam at hour 4 (second hour in the pH 7.4 buffer media),the same bead would only release 15% or less at hour 4 when tested usingthe lower pH 6.8 buffer media. This 50% reduction would also apply athour 6. Often the reduction is more significant, achieving only 35% orless, sometimes only 25% or less, of the release in pH 7.4 buffer whentested using the pH 6.8 buffer. As shown in the Examples below, EudragitFS 30 D is suitable for providing an enteric coating “designed torelease at pH 7 or higher.”

Some embodiments of the delayed sustained release lorazepam beads have arelease mechanism and enteric coating sufficient to provide 20-50%release of lorazepam at 4 hours and 50-80% release at 8 hours in the twomedia dissolution test; but less than 10% release of lorazepam at 4hours and less than 35%, preferably less than 30%, release in 8 hours inthe modified two media dissolution test using pH 6.8 buffer mediainstead of pH 7.4 buffer media.

Alternatively, the delay coating can be a time delay coating based onthickness and water solubility rather than sensitivity to pH. Generally,film formers for time-delayed release can be water soluble, dissolvingduring GI transit, or water insoluble which swell under physiologicalconditions whereupon drug release is controlled by diffusion through theswollen coating. The duration of time delay is influenced by thehydrophilic and swelling properties of the polymer and coat thickness.Examples of such polymers are cellulose acetates, ethylcellulose,glycerides, substituted methacrylates, polyvinyl acetate, HPMC, andcarboxymethylcelluloses (CMC). In some embodiments the coating containspolymers having low water solubility which slowly dissolve away. Inother embodiments, the coating contains a mixture of water soluble andwater insoluble polymers (or higher and lower water soluble polymers).By controlling the ratios of the polymers and the thickness/amount, thedesired time delay can be achieved. Examples of water soluble polymersinclude cellulose ethers such as HPMC, methylcellulose,hydroxyethylcellulose, Na CMC, and polyvinylpyrrolidone (PVP). Lesssoluble or insoluble polymers include ethylcellulose andpolymethacrylates.

In practice, the pharmaceutical composition of the invention can permita once daily dosing regimen. Controlling the amount of lorazepamprovided as (i) sustained release lorazepam beads and as (2) delayedsustained release lorazepam beads, as well as the degree of sustainedrelease and delay provided, can produce useful blood plasmaconcentration levels of lorazepam in a patient. The sustained releaselorazepam beads release the lorazepam over several hours shortly afteradministration. The delayed sustained release lorazepam beads begin thesustained release after an initial delay, typically of several hours. Insome embodiments, the delay is around 6 hours (e.g., 5-7 hours, usually5-6 hours) and/or begins in the high pH of the terminal ileum. Averagetransit time to the terminal ileum is generally considered to beapproximately 6 hours. Thus the full day's dose of lorazepam can bespread out over time to reduce blood plasma fluctuations while assuringthe minimum therapeutic concentrations are maintained. In this way,preferred compositions of the invention can provide therapeutic effectfor 24 hours under steady state conditions with once daily dosing.Quantitatively, certain preferred embodiments of the invention willprovide a blood plasma concentration of 10 ng/ml or more for at least 20hours, often at least 22 hours, and sometimes for 24 hours under steadystate conditions over a 24 hour period (e.g., from daily-dose todaily-dose).

For clarity, the term “steady state” is used in its ordinary sense inthe pharmaceutical arts. It does not mean constant, but rather thedynamic equilibrium that is obtained after consistent successiveadministrations of a drug, typically several days (e.g., 5 times the ½life, or 3-5 days in the case of lorazepam). For example, a patientalready taking lorazepam immediate release tablets on a regular schedule(two or three times per day) has lorazepam in his/her blood when thenext dose is administered. After ingestion, the dose is released and theamount of lorazepam in the blood increases to a maximum blood plasmaconcentration or “Cmax.” The lorazepam is concurrently being metabolizedand/or removed from the blood by biological actions of the body and sothe blood plasma concentration falls. The decline in drug blood plasmaconcentration will continue until the next dose of lorazepam is taken.The drug blood plasma concentration will reach its lowest concentrationlevel, the “Cmin,” just before the new dose of lorazepam is absorbedinto the blood. The new dose causes a rise in blood plasma concentrationand the cycle repeats, reaching the Cmax once again followed by a fallto the Cmin and a new administration of lorazepam, etc. In contrast tothe steady state, the first dose of lorazepam produces different bloodplasma values because no lorazepam is in the blood at the time of thedose. The Cmin for such a single dose experiment is zero at the outset.The Cmax is typically noticeably lower than the steady state Cmax.Because the present invention is applicable for chronic administrationof lorazepam (one or more weeks and perhaps months or years), the steadystate parameters can be more meaningful. Indeed, in some embodiments ofthe present invention, a single dose study (e.g., initial dose) will notprovide a therapeutic concentration in the blood stream sooner than 1hour, often not before 2 hours, and in some embodiments not before 3hours. In some embodiments, a minimum therapeutic blood plasmaconcentration can be taken to be 10 ng/ml.

Preferred embodiments provide a lorazepam blood plasma steady state Cmaxfrom daily dosing that is about equal to, or less than, the steady stateCmax obtained from dosing the same total daily amount of lorazepam viaimmediate release tablets through b.i.d or t.i.d. regimens. The term“about equal” means that the steady state Cmax of the controlled releasecomposition is within +/−35%, preferably with +/−20% of the steady stateCmax for the corresponding immediate release tablets given b.i.d. ort.i.d (having the same total daily dose). In some embodiments, thesteady state Cmax of the controlled release composition approximates, oris less than, the steady state Cmax for the corresponding immediaterelease tablets given b.i.d. The term “approximates” means +/−15%,preferably +/−10%. The lorazepam blood plasma steady state Cmin for thesustained release composition is preferably about equal to, or greaterthan, the steady state Cmin for the corresponding immediate releasetablets given b.i.d. (having the same total daily dose). In someembodiments the steady state Cmin approximates or is greater than theCmin for the corresponding immediate release tablets given b.i.d. Theterms “about equal” and “approximates” have the same meaning as regardsthe Cmax.

Though the lorazepam steady state Cmax and Cmin values of the inventivecomposition may be about equal to the Cmax and Cmin of the correspondingdose of immediate release tablets in b.i.d., the composition is believedto lower the risk of adverse events, such as sedation, somnolence,dizziness, memory impairment, etc. Beyond Cmax, the rate of increase oflorazepam blood concentration is also believed to correlate with adverseevent risk: a slower rise in lorazepam blood plasma concentration hasless risk of adverse events. The composition of the present invention ina once daily dose form provides a slower increase in lorazepam bloodconcentration than the use of immediate release tablets. This differencecan be expressed by the “Tmax,” i.e., the time to regain steady stateCmax after a dose is administered. Preferred embodiments of thepharmaceutical composition of the invention typically provide a Tmax notsooner than 4 hours, often not sooner than 6 hours, more typically notsooner than 7 hours, and often not sooner than 8 hours.

The use of two sustained release bead populations, one further having adelay before release starts, can provide for advantageouspharmacokinetic profiles. The release of drug can be effectivelysmoothed and prolonged leading to relatively flat plasma concentrationvs. time curves around the Cmax (e.g. flat tops). Often the curve willbe constant within +/−2 ng/ml variation for at least 8 hours, preferablyfor at least 10 hours, and sometimes at least 12 hours.

Another aspect of the present invention relates to a sustained releaselorazepam pharmaceutical composition, which comprises lorazepamprolonged release beads in sufficient amount and duration that in asingle dose pharmacokinetic study, the composition has a pharmacokineticprofile that comprises a Tmax at 4 hours or later and continuedabsorption of lorazepam beyond 20 hours, preferably for at least 24hours, more preferably for at least 28 hours, and still more preferablyfor at least 30 hours. The composition is an oral dosage form, such as acapsule filled with beads, containing 0.5 to 10 mg of lorazepam.Typically the composition maintains a therapeutic effect for 24 hours(in steady state) when administered in a once daily dosing regimen.

The “prolonged release beads” are any pharmaceutical particulates thatprovide long term sustained release, optionally with an initial delay.The prolonged release beads can be used as the sole bead in thecomposition or in combination with one or more other beads includingimmediate and/or sustained release beads. The prolonged release beadscan be, for example, a slow sustained release bead optionally used inconjunction with immediate release and/or relatively quick sustainedrelease beads. Or the prolonged release bead can be a hybrid bead havingtwo releases of lorazepam; i.e., a first release from an outer coatingfollowed by a sustained release from a more interior portion of thebead. The hybrid bead can be used alone or in combination with immediateand or sustained release beads. The prolonged release beads can also bethe delayed sustained release beads as described above and used inconjunction with sustained release beads and optionally with immediaterelease beads.

The prolonged release beads are present in the sustained releasecomposition in a sufficient amount and with a sufficiently prolongedrelease (duration) that absorption of lorazepam is detectable even after20 hours of a pharmacokinetic study. The study is conducted with fastingduring the administration and runs for 120 hours. The continued releaseof lorazepam from the dosage form and concomitant absorption can bededuced by comparing the loss of concentration of lorazepam in the bloodplasma to the known (or measured) elimination rate of lorazepam. As longas any appreciable amount of lorazepam is being absorbed into the body,the decline in blood plasma concentration will be slower than thefundamental lorazepam elimination rate. A comparison to theconcentration decline of an immediate release tablet can be used toconfirm or determine whether a sustained release composition has aslower decline and thus is achieving release and absorption of thelorazepam. Graphically the difference is more readily appreciated whenplotted using a log scale for concentration. The “continued absorption”refers to the relatively uninterrupted release and absorption oflorazepam provided by a sustained release composition. The absorptionmay have an initial delay, but once release and absorption begin, asustained release composition will continue to release lorazepam untilthe drug loaded dosage form is essentially exhausted. In contrast, anon-sustained release composition such as a composition that providestwo bolus doses of lorazepam, would not have “continued absorption” evenif the second bolus was released at hour 22.

By providing a sufficient amount of lorazepam in the form of theprolonged release beads and for a sufficient duration that release oflorazepam and its absorption can be seen beyond 20 hours of the singledose pharmacokinetic study, the steady state Cmin (as well as the Cmax)can be surprisingly improved. Preferably the absorption is ongoing to atleast 24 hours, more preferably at least 28 hours, still more preferablyat least 30 hours, and even at least 32 hours. While the absorption ismost likely slight as determined from a single dose pharmacokineticstudy, its cumulative effect can provide a significant increase in Cmin,Cmax, and total absorption/exposure, i.e., Area Under the Curve (AUC).Because of the prolonged release and absorption, in some embodiments,around half of the total AUC from 0-120 hours is achieved in the first24 hours of a single dose pharmacokinetic study; generally from 40-60%,often 45 to 55%, of the total AUC in 0-120 hours is achieved in hours0-24. Part of the ability to provide drug for absorption for so long isattributable to the bead or particulate form of the lorazepam. Generallythe transit time through the GI tract is 12 to 24 hours. But for beadshaving a particle size of 1 mm or less, the transit time can be muchlonger. The beads may percolate up and down the intestinal tract and/ormay get delayed in lumen tissue clefts, etc. Thus, when the nextadministration of the sustained release composition occurs, the priordose may still be releasing lorazepam. The previously describedcomposition having lorazepam sustained release beads and lorazepamdelayed sustained release beads preferably meets one or more of theseprolonged absorption and AUC goals, wherein the delayed sustainedrelease beads serve as the prolonged release beads. Likewise, thesustained release lorazepam pharmaceutical composition, which compriseslorazepam prolonged release beads, typically meets the Cmin, Cmax, andTmax values, including preferred values, as previously described for thecomposition having lorazepam sustained release beads and lorazepamdelayed sustained release beads.

A specific embodiment of the present invention relates to apharmaceutical composition that contains 2 mg of lorazepam, split aboutevenly between sustained release and delayed sustained release lorazepambeads, and provides for once daily dosing. Such a composition preferablyprovides a steady state Cmax of 26 ng/ml or less, usually 23 ng/ml orless when administered once daily. The Cmin, however, does not fallbelow therapeutic levels. Preferably the Cmin is at least 10 ng/ml,sometimes at least 11 ng/ml, and can be at least 12 ng/ml, whenadministered once daily. The Tmax is typically within the range of 4 to12 hours after once daily administration.

Typically the compositions of the present invention exhibits doseproportionality within the range of 1-6 mg of lorazepam. Theproportionality is typically with respect to the AUC (total exposure)but is also preferably found with the steady state Cmax and/or Cmin. Thefollowing approximation can apply to preferred embodiments regarding thesteady state Cmax. Each 1 mg of lorazepam provides a lorazepam bloodplasma steady state Cmax of not greater than 10 ng/ml+20%. Thus underthis embodiment, a 2 mg dose preferably provides a steady state Cmaxwithin the range of 20-24 ng/ml or less, preferably 20-24 ng/ml; a 3 mgdose preferably provides a steady state Cmax within the range of 30-36ng/ml or less, preferably 30-36 ng/ml, etc. These values assume oncedaily dosing. The lorazepam steady state Cmin is preferably at least 5ng/ml for each 1 mg of lorazepam. For example, 2 mg of lorazepampreferably has a lorazepam blood plasma steady state Cmin of at least 10ng/ml; while 4 mg of lorazepam preferably has a lorazepam blood plasmasteady state Cmin of at least 20 ng/ml; etc. Again these values assume aonce daily dosing regimen.

For clarity, all of the values for steady state Cmax, Cmin, and Tmax canbe for a single subject but more commonly are an average of multiplesubjects, e.g., multiple patients, multiple participants in abioavailability study, etc. Also, the steady state values can becalculated from a single dose pharmacokinetic study by methods known inthe art. Such calculated values (also called “simulations”) are alsosuitable for determining the steady state values for purposes of thepresent invention.

The pharmaceutical compositions of the invention can be used to treatany lorazepam-treatable condition. These conditions are most oftenrelated to the treatment or management of anxiety related disorders.Examples include, but are not limited to: Generalized Anxiety Disorderand anxiety associated with major depression. But other uses forlorazepam can also apply to this invention; e.g., PTSD, insomnia and/orsleep disorders, bipolar disorder, obsessive-compulsive disorder (OCD),social anxiety disorder, convulsions, etc. The pharmaceuticalcompositions of the present invention are generally administered onceper day. Though the dose is usually administered once daily, someclinicians may elect to divide the total daily dose amount for somepatients into one or more administrations per day.

The invention will be further described with respect to the followingnon-limiting example.

EXAMPLE 1

Sustained release lorazepam beads were made having the following nominalcomposition.

Reference to Quality Unit Composition Component Standards Functionmg/Unit^(a) % w/w Lorazepam USP Active 2.00 3.0 ingredient HypromelloseK100 USP Release control 0.67 1.0 premium LV agent Starch NF Binder 6.6710.0 pregelatinized Microcrystalline NF Filler 57.33 86.0 cellulosespecial Purified water —^(b) Total 66.67 100.0 ^(a)= Equivalent weightof core beads to obtain a 2 mg dose of Lorazepam. ^(b)= Removed duringprocessing. USP = United States Pharmacopeia; NF = National Formulary

[45] The beads were made by screening (30 mesh) the lorazepam, HPMC, andstarch and mixing for 5 minute increments. The MCC was screened (30mesh) and subsequently added with 10 minutes of mixing. The dry mixturewas granulated with the addition of water, extruded, and spheronized.The beads were dried to a residual moisture content of less than 3% w/wand fraction screened between 40 mesh and 25 mesh. Samples of the beadswere subjected to a two media in vitro dissolution test and the resultsare shown below. The average is also graphically shown in FIG. 1.

Apparatus USP Apparatus 1 Volume 900 mL Rotation Speed 100 RPMTemperature 37° C. ± 0.5° C. Medium H 0-2: 0.1N HCl Number of Units 6 H2-26 pH 7.4 Phosphate Buffer Collection Time (h) 1 2 4 6 8 10 12 14 1822 26 Percent 1 28 41 56 65 72 78 83 89 90 91 91 Dissolved 2 28 42 57 6775 80 85 86 93 94 94 3 28 40 56 65 72 78 83 89 90 92 92 4 28 42 58 67 7480 85 88 92 94 94 5 29 42 59 68 76 82 87 90 94 96 96 6 29 43 59 68 75 8186 89 93 94 94 Mean 28 42 58 67 74 80 85 88 92 94 94 RSD 2.2 2.2 2.4 2.02.3 2.0 1.9 1.9 1.8 1.9 1.9 RSD = Relative Standard Deviation.

EXAMPLE 2

Delayed sustained release lorazepam beads were made by using the abovesustained release lorazepam beads and applying an enteric coating. Theenteric coating was designed to release at pH 7 or higher andspecifically was intended to permit free release at pH 7.4. Theresulting delayed sustained release lorazepam beads have the followingnominal composition.

Reference to Quality Unit Composition Component Standards Functionmg/Unit^(a) % w/w Example 1 beads USP Active ingredient 66.7 82.11(core) Eudragit FS 30D Delayed release 12.1 14.92 control agentPlasACRYL T20 Plasticizer 1.21 1.49 Colloidial silicon USP Anti-tacking1.20 1.48 dioxide (optional) agent Purified water —^(b) Total 81.21100.0 ^(a)= Equivalent weight of coated beads to obtain a 2 mg dose ofLorazepam. Coating level is for a 20% weight gain. ^(b)= Removed duringprocessing. USP = United States Pharmacopeia.

The delayed sustained release lorazepam beads were made by coating thebeads obtained according to example 1. The Eudragit, plasticizer, andwater were mixed and screened (35 mesh) to form a coatingsolution/suspension. The core beads were coated with the coatingsolution/suspension using a Glatt fluid bed drier. The optionalcolloidal silicon dioxide can be further coated via a spray drier. Thecoated beads are then dried and oversized beads are removed by using an18 mesh screen cutoff.

Samples of the delayed sustained release lorazepam beads were subjectedto the two media in vitro dissolution test using pH 7.4 buffer media andthe results are summarized below. The average result is graphicallyrepresented in FIG. 2.

Apparatus USP Apparatus 1 Volume 900 mL Rotation Speed 100 RPMTemperature 37° C. ± 0.5° C. Medium H 0-2: 0.1N HCl Number of Units 6 H2-26: pH 7.4 Phosphate Buffer Collection Time (h) 1 2 4 6 8 10 12 14 1822 26 Percent 1 1 2 34 52 64 73 80 86 93 97 99 Dissolved 2 0 1 31 48 5968 75 81 88 97 95 3 0 1 32 49 60 69 76 81 88 91 93 4 1 1 33 51 62 71 7883 89 92 93 5 1 1 32 49 61 70 77 82 88 92 93 6 1 1 32 50 62 71 78 83 9195 97 Mean 1 1 32 49 61 70 77 82 89 93 95 RSD 27.0 20.6 3.2 3.0 2.9 2.52.3 2.3 2.3 2.4 2.7 RSD = Relative Standard Deviation.

For comparison, samples of the delayed sustained release beads weresubjected to a modified two media in vitro dissolution test where the pH7.4 buffer media was replaced with a pH 6.8 buffer media. The resultsare summarized below and the average is graphically shown in FIG. 3.

Apparatus USP Apparatus 1 Volume 500 mL Rotation Speed 100 RPMTemperature 37° C. ± 0.5° C. Medium H 0-2: 0.1N HCl Number of Units 6 H2-26: pH 6.8 Phosphate Buffer Collection Time (h) 1 2 4 6 8 10 12 14 1822 26 Percent 1 0 1 4 11 21 33 46 57 73 83 92 Dissolved 2 0 1 3 8 17 2840 51 67 78 87 3 0 1 4 10 20 30 42 53 68 79 87 4 0 1 4 9 19 30 42 53 6980 88 5 0 1 4 9 18 28 40 51 67 77 85 6 0 1 3 9 18 29 41 52 67 79 87 Mean0 1 4 9 19 30 42 53 69 79 88 RSD 13.5 17.8 16 11.6 7.8 6.8 5.1 4.4 3.22.7 2.6 RSD = Relative Standard Deviation.

As can be seen from the above results, the delayed sustained releasebeads showed a significant reduction in the amount released at hours 4and 6 in the pH 6.8 buffer in comparison to the pH 7.4 buffer used inthe two media test dissolution test.

EXAMPLE 3

A pharmaceutical composition containing sustained release lorazepambeads and delayed sustained release lorazepam beads was formed byfilling a capsule with the beads of Examples 1 and 2. A hard gelatincapsule was filled with the following nominal amounts of ingredients toform a 2 mg lorazepam oral dosage form.

Reference to Quality Unit Composition Component Standards Functionmg/Unit % w/w Example 1 beads 33.33 45.09% Example 2 beads 40.60 54.91%Hard gelatin capsule shell Capsule 1 unit — Total 73.93 100.0 ^(a)= 2 mgLorazepam dose. The contribution is 50% from the Example 1 beads and 50%from the Example 2 beads.

The nominal 2 mg lorazepam capsules were evaluated in a single dosepharmacokinetic study involving 24 subjects. The dose was administeredunder fasting conditions. The study lasted for 120 hours. The studyaverage showed that lorazepam was being absorbed beyond 30 hours. Thecalculated steady state values show that therapeutic concentrations oflorazepam are maintained over a 24 hour period by once daily dosing ofthe 2 mg lorazepam capsules of the invention. The steady state Cmax andCmin are each about equal to the corresponding Cmax and Cmin achievedwith a b.i.d. dosing regimen of 1 mg immediate release lorazepam tablets(1 mg per 12 hours equals 2 mg per day).

Each of the patents and articles mentioned above are incorporated hereinby reference. The invention having been described it will be obviousthat the same may be varied in many ways and all such modifications arecontemplated as being within the scope of the invention as defined bythe following claims.

1.-20. (canceled)
 21. A pharmaceutical composition comprising (i)lorazepam sustained release beads comprising lorazepam dispersed in apolymer matrix; and (ii) lorazepam delayed sustained release beadscomprising (a) a core comprising lorazepam dispersed in a polymer matrixand (b) a delayed release coating surrounding the core, wherein theratio of the lorazepam sustained release beads to the lorazepam delayedsustained release beads is from 1:0.7 to 1.3, based on the weight of thelorazepam.
 22. The pharmaceutical composition of claim 21, wherein thelorazepam sustained release beads and the core of the lorazepam delayedsustained release beads independently comprise 1 to 4% w/w lorazepam.23. The pharmaceutical composition of claim 21, wherein the compositioncomprises a total amount of lorazepam of 0.5 to 6 mg.
 24. Thepharmaceutical composition of claim 21, wherein the compositioncomprises a total amount of lorazepam of 2 mg.
 25. The pharmaceuticalcomposition of claim 21, wherein about half of the lorazepam present isprovided in the sustained release beads and about half of the lorazepampresent is provided in the delayed sustained release beads.
 26. Thepharmaceutical composition of claim 21, wherein all of the lorazepampresent in the composition is present in the sustained release beads andthe delayed sustained release beads.
 27. The pharmaceutical compositionof claim 21, wherein the polymer matrices of the sustained release beadsand the delayed sustained release beads independently comprise one ormore polymers selected from the group consisting ofhydroxypropylmethylcellulose, polyacrylates, and polyethylene oxides.28. The pharmaceutical composition of claim 27, wherein the polymermatrices of the sustained release beads and the delayed sustainedrelease beads independently further comprises one or more binders and/orone or more fillers.
 29. The pharmaceutical composition of claim 27,wherein the sustained release beads have a dissolution profile in a twomedia in vitro dissolution test such that from 20 to 70% of thelorazepam is released in 2 hours, wherein the two media in vitrodissolution test is carried out for two hours in a media that comprises0.1 N HCl and then is carried out in a media that comprises a phosphatebuffer and has a pH of 7.4.
 30. The pharmaceutical composition of claim21, wherein the delayed release coating is an enteric coating.
 31. Thepharmaceutical composition of claim 30, wherein the delayed releasecoating is designed to release lorazepam at pH 6 or higher.
 32. Thepharmaceutical composition of claim 30, wherein the delayed releasecoating is designed to release lorazepam at pH 6.8 or higher.
 33. Thepharmaceutical composition of claim 30, wherein the delayed releasecoating is designed to release lorazepam at pH 7 or higher.
 34. Thepharmaceutical composition according to claim 30, wherein the delayedsustained release beads have a dissolution profile in a two media invitro dissolution test such that 90% release of the lorazepam occursafter 6 hours, wherein the two media in vitro dissolution test iscarried out for two hours in a media that comprises 0.1 N HCl and thenis carried out in a media that comprises a phosphate buffer and has a pHof 7.4.
 35. The pharmaceutical composition of claim 21, wherein thedelayed release coating is a pH-independent delayed release coating. 36.The pharmaceutical composition of claim 21, wherein the delayed releasecoating is a pH-independent delayed release coating comprising one ormore polymers selected from the group consisting of cellulose acetates,cellulose ethers, ethylcellulose, glycerides, substituted methacrylates,polyvinyl acetates, and polyvinylpyrrolidone.
 37. The pharmaceuticalcomposition according to claim 35, wherein the delayed sustained releasebeads have a dissolution profile in a two media in vitro dissolutiontest such that the release of 90% of the lorazepam occurs after 10hours, wherein the two media in vitro dissolution test is carried outfor two hours in a media that comprises 0.1 N HCl and then is carriedout in a media that comprises a phosphate buffer and has a pH of 7.4.38. The pharmaceutical composition of claim 21, wherein the delayedrelease coating comprises a polymer and one or more plasticizers and/orone or more anti-tack agents.
 39. The pharmaceutical composition ofclaim 21, wherein the lorazepam sustained release beads and thelorazepam delayed sustained release beads are provided in a capsule orsachet.
 40. A method of treating an anxiety related disorder comprisingadministering a composition according to claim 21 to a subject in needthereof.
 41. The method of claim 40, wherein the anxiety relateddisorder is General Anxiety Disorder.
 42. The method of claim 40,wherein the composition is administered once per day.